Oral bioavailability is the main decisive factor in achieving the desired systemic drug concentration, and it can be increased by developing novel dosage forms that can avoid first-pass metabolism. The current study aimed to employ the quality-by-design (QbD) approach to develop and optimize the therapeutically efficient instant release buccal films (IRBFs) of eletriptan, which should not only be able to avoid the first-pass metabolism, but also circumvent the condition of gastric stasis which is associated with migraine. The solvent casting method was employed to fabricate IRBFs, including hydroxypropyl methylcellulose E-5 (HPMC E5) as a polymer, glycerin as a plasticizer and permeation enhancer, and tween-80 (T80) as a surfactant. The prepared films were subjected to different physicochemical characterizations using Fourier transform infrared spectroscopy (FTIR), surface morphology, disintegration time (DT), in vitro, and ex vivo permeation studies. The findings have shown that prepared films were rapidly disintegrating (DT < 30 s), immediately dissolving (TDT < 120 s), and instantly releasing and allowing rapid permeation of the drug. The outcomes of the study have assisted to develop the optimized formulation, followed by its characterization, which showed that the findings were quite similar to those, predicted by the statistical tool for the optimized formulation. The similarity of predicted and obtained results have confirmed the reproducibility of the prepared IRBFs. [ABSTRACT FROM AUTHOR]